Downloaded from http://heart.bmj.com/ on March 6, 2016 - Published by group.bmj.
com
< An additional appendix is
published online only. To view
this file please visit the journal
online (http://heart.bmj.com).
1
Surgical Epidemiology Unit,
Department of Biosurgery and
Surgical Technology, Imperial
College London, St Mary’s
Hospital, London, UK
2
Adult Congenital Heart Centre,
Royal Brompton Hospital
National Heart and Lung
Institute, Imperial College
London, Royal Brompton
Hospital, London, UK
3
Cellular Electrophysiology
Group, Harefield Heart Science
Centre, National Heart and Lung
Institute, Imperial College
London, Harefield Hospital, UK
4
Cardiac Electrophysiology,
National Heart and Lung
Institute, Imperial College
London, St Mary’s Hospital,
London, UK
5
Department of Cardiology,
National Heart and Lung
Institute, Imperial College
London, The Hammersmith
Hospital, London, UK
6
Department of Biomolecular
Medicine, Imperial College
London, Sir Alexander Fleming
Building, London, UK
7
Adult Congenital Heart Centre,
Royal Brompton Hospital
National Heart and Lung
Institute, Imperial College
London, Royal Brompton
Hospital, London, UK
8
Department of Cardiothoracic
Surgery, National Heart and
Lung Institute, Imperial College
London, The Hammersmith
Hospital, London, UK
Correspondence to
Srdjan Saso, Clinical Research
Fellow, Department of
Biosurgery and Surgical
Technology, 10th Floor, QEQM
Wing, St Mary’s Hospital,
London W2 1NY, UK;
srdjan.saso@imperial.ac.uk
Accepted 8 September 2010
Heart 2010;96:1789e1797. doi:10.1136/hrt.2010.204933
Atrial septal defect closure is associated with
a reduced prevalence of atrial tachyarrhythmia in
the short to medium term: a systematic review and
meta-analysis
Joshua A Vecht,1 Srdjan Saso,1 Christopher Rao,1 Konstantinos Dimopoulos,2
Julia Grapsa,1 Cesare M Terracciano,3 Nicholas S Peters,4 Petros Nihoyannopoulos,5
Elaine Holmes,6 Michael A Gatzoulis,7 Thanos Athanasiou8
ABSTRACT
Atrial tachyarrhythmias are a common complication of
atrial septal defects. The objective was to determine the
effect of atrial septal defect closure on pre-existing atrial
tachyarrhythmias and to investigate if such an effect is
present after either surgical or percutaneous closure.
Medline, EMBASE, Cochrane Library, and Google Scholar
databases were searched between 1967 and 2009. The
search was expanded using the ‘related articles’ function
and reference lists of key studies. All studies reporting
pre- and post- closure incidence (or prevalence) of atrial
tachyarrhythmias in the same patient groups were
included. Data were independently extracted by two
authors according to a pre-defined protocol. Incongruities
were settled by consensus decision. Twenty six studies
were identified including 1841 patients who underwent
surgical closure and 945 who underwent percutaneous
closure. Meta-analysis using a random effects model
demonstrated a reduction in the prevalence of atrial
tachyarrhythmias following atrial septal defect closure
[OR ¼ 0.66 (95% CI 0.57-0.77)]. This effect was
demonstrated after both percutaneous [OR ¼ 0.49 (95%
CI 0.32-0.76)] and surgical closure [OR ¼ 0.72 (95% CI
0.60-0.87)]. Immediate (<30 days) and mid-term (30
days - 5 years) follow-up also demonstrated a reduction
in AT prevalence [ORs of 0.80 (95% CI 0.66-0.97) and
0.47 (95% CI 0.36-0.62) respectively]. Atrial septal
defect closure, whether surgical or percutaneous, is
associated with a reduction in the post-closure
prevalence of pre-existing atrial tachyarrhythmias and
atrial fibrillation in the short to medium term.
INTRODUCTION
Atrial septal defects (ASDs) are one of the most
common congenital cardiac abnormalities in
adulthood associated with arrhythmias, right heart
failure, stroke and premature death.1 While large
ASDs may present in childhood with signs of heart
failure, a significant proportion of patients present
in the 3rde4th decade of life.2 Often asymptomatic
until the onset of complications, the main cause of
morbidity and mortality in ASD patients is attrib-
uted to the development of atrial tachyarrhythmia
(AT).1 3 4 Approximately 10% of untreated patients
with ASD develop supraventricular arrhythmias,
especially atrial fibrillation (AFIB) by the age of
40 years,3 5 and the incidence continues to increase
Review
with age (reported incidence for older patients is
20e50%).6e8
Initially, all ASDs were closed surgically but
percutaneous techniques first described in 1974 by
King and Mills9 have become established alterna-
tives. According to the National Institute of Clinical
Excellence and the Joint American Heart Associa-
tion/American College of Cardiology guidelines,
percutaneous techniques are now considered
‘acceptable treatment’ (for ostium secundum
ASD).10 Sinus venosus, coronary sinus, or ostium
primum ASD, however, are unsuitable for percuta-
neous closure and thus need to be closed surgically.11
Previous studies have examined the impact of ASD
closure on AT,12 suggesting that closure may initiate
or discontinue AT,6 but comprehensive analysis has
not been performed to quantitatively review the
available evidence. To date, there is no randomised
trial comparing surgical and percutaneous closure
and now that percutaneous management has
become widely established, this is unlikely to occur.
Consequently the specific aims of this study
were: (a) to determine the potential antiarrhythmic
effect of ASD closure on pre-existing AT; (b) to
determine whether evidence for an antiarrhythmic
effect is seen following both surgical and percuta-
neous ASD closure; and (c) to determine whether
any antiarrhythmic effect is time dependent.
METHODS
Literature search
A multilayer literature search was performed using
Medline, EMBASE, Cochrane Library and Google
Scholar databases for all relevant studies until 2009
using the following MeSH search headings: ((Atrial
Septal Defect (ASD) or ASD closure or ASD Repair)
and (Cardiac Surgery or Cardiothoracic surgery or
Trans-catheterisation) and (Rhythm or Atrial (Tachy)
Arrhythmia or Atrial Fibrillation (AFIB) or Flutter)).
The search was expanded using the ‘related articles’
function and by considering reference lists of the
key studies. Abstracts from the American Heart
Association were also searched. All the review
articles whose subject was ASD closure, as well as
their reference lists were also screened (figure 1).
Outcomes
The primary outcome measure is change in the
prevalence of AT following ASD closure. In this
1789
 Downloaded from http://heart.bmj.com/ on March 6, 2016 - Published by group.bmj.com

Review

63 additional records identified

analysis, papers were included which referred to ‘atrial tachy-
512 studies identified in initial
through references and related arrhythmia’, ‘atrial fibrillation’, ‘atrial flutter’, ‘atrial tachy-
Identification

search
articles
cardia’, ‘left atrial tachycardia’, ‘atrio-ventricular nodal re-entry
tachycardia’, ‘junctional tachycardia’, ‘Wolff-Parkinson-White’
and ‘supraventricular tachycardia’. Secondary analysis of studies
575 reports fulfilling inclusion criteria (after duplicates removed) which referred only to ‘atrial fibrillation’ was also performed.
Screening

Inclusion and exclusion criteria

575 reports screened 480 reports excluded We included all studies reporting the incidence (or prevalence) of
AT before and after ASD closure (only patients with pre-existing
AT within studies were included). All studies reporting an adult
Eligibility

69 full-text articles excluded

population in which the mean/median age was at least 18 years
95 full-text articles assessed for eligibility
on exclusion criteria prior to intervention were included. Studies of both surgical and
percutaneous closure including all ASD types (sinus venosus,
ostium primum and ostium secundum) were included. Studies
26 studies included in qualitative analysis (meta-analysis)
describing patent foramen ovale closure, those not written in
English and those failing to differentiate between new-onset AT
and a diminution in the prevalence of pre-closure ATwere excluded.
Included

Surgical
Closure
(19 studies) Data extraction
Two reviewers (SS and JV) independently extracted data according
to a predefined search protocol. This included study design, type of
Percutaneous
Closure ASD and AT, number of patients, age of patients, and closure type.
(7 studies) The prevalence of AT and AFIB was recorded pre-closure, post-
closure and at latest follow-up. In the case of discrepancy,
Figure 1 Search strategy and selection of studies (PRISMA statement consensus decision was achieved by discussion, and where
compliant). necessary adjudication by a third reviewer (TA) (tables 1 and 2).

Table 1 Studies comparing the prevalence of atrial tachyarrhythmia/fibrillation between pre-closure and post-closure groups in a generalised
population
Number Mean age AT prevalence AF prevalence
Study Type(s) Type of patients of patients (pre-, post- (pre-, post- Type of
Author (year) design of ASD of AT (AT, no AT) (years) closure) (%) closure) (%) closure
Taniguchi et al13 (2009) R AS AF 9 (9, 0) 68.1* 100, 100 100, 100 P
Giardini et al14 (2008) R NS AFF 134 (13, 121) 39 10, 3.7 NS P
Wilson et al15 (2008) R NS AFF, AT, SVT, O 202 (22, 180) 33.3 10.9, 5.0 NS P
Spies et al16 (2008) R OS AF 240 (53, 187) 47 22.1, 19.6 22.1, 19.6 P
Silversides et al17 (2008) P OS AFF, SVT 200 (40, 160) 50 20.0, 6.5 NS P
Silversides et al18 (2004) R OS AFF 132 (20, 112) 44 15.0, 8.3 NS P
Suarez de Lezo et al19 (2000) R NS AF 28 (3, 25) 36 10.7, 7.1 10.7, 7.1 P
Erkut et al20 (2007) P OS AF 41 (6, 35) 44 14.6, 12.2 14.6, 12.2 S
Piechowiak et al21 (2006) R OS AF 93 (22, 71) 37 23.7, 23.7 23.7, 23.7 S
Mantovan et al22 (2003) R OP, OS, SV AF, SVT 136 (12, 124) 36.8 8.8, 7.4 8.1, 7.4 S
Ghosh et al23 (2002) R OS AF 89 (29, 60) 48.6 32.6, 18.0 32.6, 18.0 S
Donti et al24 (2001) R OS AFF 53 (14, 39) 57 26.4, 26.4 NS S
Jemielity et al25 (2001) R OS AF 76 (4, 72) 45.8 5.3, 5.3 5.3, 5.3 S
Gatzoulis et al7 (1999) R OP, OS, SV AF, AFl 213 (40, 273) 41 18.8, 11.3 NS S
Berger et al2 (1999) R OS, SV AF, AFl 211 (46, 165) 42.2 21.8, 14.7 13.3, 10.0 S
Shibata et al26 (1996) R OS AF 49 (24, 25) 57.4 49.0, 32.7 49.0, 32.7 S
Konstantinides et al27 (1995) R OP, OS, SV AFF 84 (22, 62) 56 26.2, 26.2 NS S
Shah et al28 (1994) P OS, SV AF 48 (12, 36) 36.2 25.0, 25.0 25.0, 25.0 S
Speechly-Dick et al29 (1993) R OS AF 55 (6, 49) 33 10.9, 10.9 10.9, 10.9 S
Murphy et al4 (1990) R OS, SV AFF 123 (19, 104) 26 15.4, 10.6 NS S
Cowen et al30 (1990) R OS AF 31 (16, 15) 57 51.6, 38.7 51.6, 38.7 S
Brandenburg et al31 (1983) R OS AF, AFl, SVT 188 (27, 161) 52.7 14.4, 10.6 8.5, 8.0 S
Lomholt et al32 (1980) R OS AF, AFl 28 (9, 20) >40 32.1, 21.4 28.6, 21.4 S
Esscher et al33 (1977) R OS AFF 166 (9, 157) 23 5.4, 5.4 NS S
Saksena et al34 (1970) R OS AF 24 (11, 13) 51* 45.8, 45.8 45.8, 45.8 S
Aldridge & Yao35 (1967) R OS AF, AFl 133 (17, 116) 32.1 12.8, 9.8 10.5, 7.5 S
*Age is given as a median.
ASD, atrial septal defect.
Study design: P, prospective; R, retrospective.
Types of atrial tachyarrhythmia: AF, atrial fibrillation; AFl, atrial flutter; AFF, atrial fibrillation and flutter; AT, atrial tachycardia; O, other: AVNRT, junctional tachycardia, Wolff-Parkinson-White;
SVT, supraventricular tachycardia.
Types of atrial septal defect: OP, ostium primum; OS, ostium secundum; SV, sinus venosus.
Types of closure: P, percutaneous; S, surgical; NS, not specified.

1790 Heart 2010;96:1789e1797. doi:10.1136/hrt.2010.204933

 Downloaded from http://heart.bmj.com/ on March 6, 2016 - Published by group.bmj.com

Review

Quality scoring Assessment of data validity and heterogeneity

Qualitative data to assess study comparability and enable
quality scoring were also extracted. These data were split into
two sections: variables previously highlighted to predispose
surgical patients to AFIB (age, gender, hypertension, diabetes,
ejection fraction, chronic obstructive pulmonary disease, left
main stem disease and three vessel coronary artery disease); and
variables known to positively affect the incidence of post-closure
AT in patients with AT (right atrial dilatation, right ventricular
dilatation and pulmonary hypertension).15 36 Table 3 summa-
rises the distribution of these risk factors. The individual inclu-
sion and exclusion criteria utilised by the studies analysed are
shown in the Appendix.
Statistical analysis
Meta-analysis was conducted according to PRISMA, MOOSE
and Cochrane Collaboration guidelines.37e39 The OR was used
as the summary statistic. An OR <1 suggested that the preva-
lence of AT was lower following ASD closure. The OR was
considered statistically significant at the p<0.05 level if the 95%
CI did not include the value 1.
Aggregation of the overall rates of the primary and secondary
outcomes was performed with the ManteleHaenszel method.40
We used a random-effects model which assumes that there is
variation between studies as this model better accounts for
heterogeneity between studies.41 42 Analysis was conducted
using Review Manager V.5.2 (The Cochrane Collaboration,
Software Update, Oxford, UK).
Several quantitative and graphical methods were used to assess,
explain and account for important determinants of meta-analytical
validitydheterogeneity and bias.
Bias exploration: publication bias and risk of bias analysis
Publication bias was assessed graphically with funnel plots to
assess for asymmetry and evidence of outliers. The assessment
of risk of bias was conducted in line with recommendations
from the Cochrane guidelines.37 We performed a ‘domain-based
evaluation’ in which critical assessments were made separately
for different domains where each domain type assessed a specific
bias type. Adequate sequence generation, allocation concealment
and blinding were not considered as we were not directly
comparing two interventions, and we only considered the effect
of selective reporting, incomplete outcome data and other
sources of bias.
Sensitivity analysis through examination of subgroups
Sensitivity analysis was performed through examination of
a number of subgroupsdsurgical ASD closure, percutaneous
ASD closure, post-closure AFIB prevalence, post-closure AT
prevalencedduring follow-up (immediate (<30 days), mid-term
(30 dayse5 years), late (>5 years)) and study quality. To quan-
tify the study quality, we devised a scoring system. We attrib-
uted a point to each study when compliant with 10 specified
factors (table 3). This generated a median of 2. The range was
then divided into thirds which were scored from 1 to 3. Ten

Table 2 Prevalence of atrial tachyarrhythmia (AT) during follow-up period

Mean Immediate AT Mid-term AT Late AT
follow-up prevalence (%) prevalence (%) prevalence (%)
Author (years) (<30 days) (>30 dayse5 years) (>5 years)
Taniguchi et al13 0.9 NS 100 NS
Giardini et al14 4.8 6.0 3.7 NS
Wilson et al15 1.8 NS 5.0 NS
Spies et al16 0.5 22.1 NS NS
Silversides et alz 17 1.9 NS 6.5 NS
Silversides et aly 18 1.4 15.0 8.3 NS
Suarez de Lezo et al19 0.7 7.1 7.1 NS
Erkut et al20 4.2 12.2 12.2 NS
Piechowiak et al21 6.6 23.7 NS 23.7
Mantovan et al22 5.7 NS NS 7.4
Ghosh et al23 4.7 NS 18.0 NS
Donti et al24 9 NS NS 26.4
Jemielity et al25 6.9 NS NS 5.3
Gatzoulis et al7 3.8 13.1 11.3 NS
Berger et al2 NS 21.3 NS NS
Shibata et al26 9.7 40.8 NS 32.7
Konstantinides et al27 8.9 NS NS 26.2
Shah et al28 25.0 NS NS 25.0
Speechly-Dick et al29 2* 10.9 10.9 NS
Murphy et al4 27.2 NS NS 10.6
Cowen et al30 3.0 38.7 NS NS
Brandenburg et al31 12 4.8 NS 10.6
Lomholt et al32 3.7 NS 21.4 NS
Esscher et al33 12 5.4 NS 5.4
Saksena et al34 6 45.8 NS 45.8
Aldridge and Yao35 NS 12.8 NS NS
*Follow-up is given as a median.
yLabelled Silversides - 1 in the figures.
zLabelled Silversides - 2 in the figures.
NS, not specified.

Heart 2010;96:1789e1797. doi:10.1136/hrt.2010.204933 1791

 Downloaded from http://heart.bmj.com/ on March 6, 2016 - Published by group.bmj.com

Review

Table 3 Distribution of risk factors for atrial tachyarrhythmia within patient groups
Author A B C D E F G H I J Total matched factors Study score
Taniguchi et al13
* * * * 4 3
Giardini et al14 * * 2 2
Wilson et al15 * * * 3 2
Spies et al16 * * * * * 5 3
Silversides et al17 * * * * * 5 3
Silversides et al18 * * * 3 2
Suarez de Lezo et al19 * * 2 2
Erkut et al20 * * * * * 5 3
Piechowiak et al21 * * * * 4 3
Mantovan et al22 * * 2 2
Ghosh et al23 * * * * 4 3
Donti et al24 * * 2 2
Jemielity et al25 * * * * 4 3
Gatzoulis et al7 * * 2 2
Berger et al2 * * 2 2
Shibata et al26 * * * 3 2
Konstantinides et al27 * * * * 4 3
Shah et al28 * * 2 2
Speechly-Dick et al29 * 1 1
Murphy et al4 * * 2 2
Cowen et al30 * * * 3 2
Brandenburg et al31 * * * 3 2
Lomholt et al32 * * * 3 2
Esscher et al33 * * 2 2
Saksena et al34 * * * * * 5 3
Aldridge and Yao35 * * * * 4 3
*Indicates that a particular factor has been reported.
Variables predisposing to atrial tachyarrhythmia in surgical patients: A, age; B, male gender; C, hypertension;, D, diabetes mellitus; E, ejection fraction; F, chronic obstructive pulmonary
disease; G, advanced coronary artery disease.
Variables that affect the incidence of post-closure atrial tachyarrhythmia in patients with diagnosed pre-closure atrial tachyarrhythmia: H, right atrial dimension/dilatation; I, right
ventricular dimension/dilatation; J, pulmonary hypertension.
Study score: 1, matched for 0e1 factors; 2, matched for 2e3 factors; 3, matched for 4e5 factors.

studies qualified for the ‘top’ third (4e5 matched factors) and calculated OR for AFIB was 0.77 (95% CI 0.63 to 0.95), with an
these studies were analysed separately. I2 of 0% throughout (figure 3).

Heterogeneity assessment through the I2 statistic Sensitivity analysis

Heterogeneity of treatment effects between studies was assessed
using the I2 statistic. This represents the proportion of total
variation observed between the trials attributable to differences
between trials rather than sampling error or chance. The degree
of heterogeneity was graded as low (I2<25%), moderate
(I2¼25e75%) or high (I2>75%).43
RESULTS
Selected studies
Literature search identified 575 manuscripts. On screening
the abstracts 480 were excluded. A further 69 were excluded
after full text review. This resulted in a final study group of
26 studies published between 1967 and 2009 being selected
for the meta-analysis. In total 2786 patients were included
from 3 prospective observational and 23 retrospective studies
(figure 1).2 4 7 13e35 Table 1 shows characteristics of individual
studies included.
Meta-analysis
Four of the 26 studies showed a statistically significant reduction
in the prevalence of AT following ASD closure.7 15 17 23 Meta-
analysis of all 26 studies showed a significant reduction in the
prevalence of AT (figure 2A), with an OR of 0.66 (95% CI 0.57 to
0.77) and an I2 of 0% indicating non-significant heterogeneity.
Seventeen of 26 studies reported the prevalence of AFIB as
a subset of overall AT prevalence.2 13 16 19e23 25 26 28e32 34 35 The
Effect of closure method
Seven studies reported percutaneous ASD closure.13e19 An OR
of 0.49 (95% CI 0.32 to 0.76) was calculated, with a moderate
heterogeneity I2 of 45% (figure 2B). Similarly when analysis of
the 19 studies reporting surgical ASD closure was performed,
the calculated OR was 0.72 (95% CI 0.60 to 0.87), with
a non-significant I2 heterogeneity of 0% (figure 2C).2 4 20e35 44
The results were similar in the surgical group when only AFIB
was considered with an OR of 0.75 (95% CI 0.60 to 0.95).
However, in the percutaneous closure group, while the OR
was similar (OR 0.85), this did not reach statistical significance
(95% CI 0.55 to 1.30).
Duration of effect
Fifteen studies2 7 14 16 18e21 26 29e31 33e35 reported AT prevalence
immediately after the procedure (<30 days), with an OR for ASD
closure of 0.80 (95% CI 0.66 to 0.97). Eleven studies7 13e20 23 29 30 32
reported AT prevalence at mid-term follow-up (30 dayse
5 years), with an OR of 0.47 (95% CI 0.36 to 0.62). Eleven
studies4 21 22 25e28 31 33 34 reported the results of long-term
follow-up (>5 years). In these, the effect of ASD closure on AT
prevalence was not significant (OR 0.84, 95% CI 0.65 to 1.07).
Study quality
Table 3 shows the number of risk factors for post-closure
AT that are matched in each study. This table also shows the
‘quality score’ assigned, based on the number of factors

1792 Heart 2010;96:1789e1797. doi:10.1136/hrt.2010.204933

 Downloaded from http://heart.bmj.com/ on March 6, 2016 - Published by group.bmj.com

Review

Figure 2 Meta-analysis of studies

comparing prevalence of atrial
tachycardia pre- and post-closure. (A)
All studies. (B) Percutaneous closure
studies only. (C) Surgical closure studies
only.

matched. Ten studies matched $4 factors scoring 3 points
for quality.13 16 17 20 21 23 25 27 34 35 In this group the OR for
prevalence of post-closure AT was 0.70 (95% 0.51 to 0.97).
Publication bias and risk of bias
Publication bias was explored with a funnel plot (figure 4A)
which shows mild asymmetry with one outlier.
Risk of bias was presented as methodological quality
graphs. Figure 4B represents the risk of bias in which each
methodological quality domain is presented as a percentage
across all included studies. Figure 4C is a methodological
quality summary depicting the scoring for each domain across
all the included studies, demonstrating mixed potential risk
of bias.

Heart 2010;96:1789e1797. doi:10.1136/hrt.2010.204933 1793

 Downloaded from http://heart.bmj.com/ on March 6, 2016 - Published by group.bmj.com
Review
Figure 3 Meta-analysis of studies
comparing prevalence of atrial fibrillation
pre- and post-closure.
DISCUSSION
This study shows that ASD closure, whether surgical or percu-
taneous, reduces the post-closure prevalence of pre-existing AT
in the short to mid term (OR 0.66, 95% CI 0.57 to 0.77). A
similar effect is also seen in the surgical but not the percuta-
neous group, when only AFIB was considered (OR 0.77, 95% CI
0.63 to 0.95), but does not seem to persist when studies with
longer-term follow-up are analysed.
Interpretation
The presence of an ASD alone has been shown to be associated
with the development of AT in 10% of patients by the age
of 40 years. Preclosure incidence of AT is estimated to be
approximately 20%.3 6 7
AT in patients with ASD is the result of cardiac remodelling
secondary to longstanding haemodynamic overload. Sizeable
ASD results in increased atrial size and stretch,7 12 45e50 right
ventricular dilatation and dysfunction,7 elevation in pulmonary
arterial pressure7 and tricuspid and mitral regurgitation.51
Atrial remodelling results in interstitial fibrosis and endo-
epicardial dissociation which predisposes to arrhythmias
(electrophysiological and structural remodelling).45 48 Electro-
physiological remodelling manifests as non-uniform changes in
the atrial effective refractory periods, conduction delays at the
crista terminalis and impaired sinus node function.45 48e50 In
addition, specific ion channel expression profiles representing ion
channel remodelling have been demonstrated in AFIB.52e54
The effect of ASD closure on the risk of arrhythmia is likely to
be the result of negative remodelling of the atria and right
ventricle, which occurs after repair. Dramatic changes such as
a reduction in right atrial and ventricular volume, an increase in
right ventricular ejection fraction and an increase in left
ventricular volume have been described following ASD
closure.55 56 As ASD closure appears to result in partial or
complete reversal of the associated haemodynamic changes, it is
possible that it may also initiate reverse remodelling processes,
and may explain the antiarrhythmic effect of ASD closure. Ion
1794
channel expression has been shown to revert in those who
electrically cardiovert,52 53 and reversal of electrical remodelling
is known to occur sooner than structural reversal,57 with animal
studies showing almost immediate electrical reverse remodelling
but persistent structural remodelling at four months.58 This is
supported by our finding of a larger effect of ASD closure on AT
at mid-term follow-up (OR 0.47, 95% CI 0.36 to 0.62) compared
to the immediately post-repair period (OR 0.80, 95% CI 0.66 to
0.97), when remodelling has not yet occurred.57 60 However, the
effect of ASD repair was lost at longer follow-up, suggesting
that other mechanisms are in action (eg, ageing). We propose
that such changes may be associated with the type of structural
remodelling which is not reversible. This is with the acknowl-
edgement that the long term data was not available for the
majority of the larger and higher quality studies. This may have
had a consequential statistical effect, so this interpretation is
proposed with caution.
Care should also be exercised when comparing results from
these different populations as studies with longer follow-up
periods were more likely to include patients who underwent
surgical closure, and had larger defects and more long-lasting ATs.
In fact 29% of patients undergoing ASD closure have persistently
increased right ventricular dimensions late after repair.7 56 This is
likely to be due to incomplete reverse remodelling and could
account for the persistence of AT in numerous patients.
A reduction in the prevalence of AT was seen after both
surgical and percutaneous closure. This is consistent with
previous studies which have not demonstrated any difference in
remodelling between closure methods.56
Strengths and limitations
This study is the first systematic review and quantitative anal-
ysis of the evidence on the antiarrhythmic effect of ASD closure.
As the best available evidence was evaluated within a robust
statistical framework, this study provides accurate estimates of
treatment effects in a clinical group in which adequately
powered experimental studies are impossible due to the low
Heart 2010;96:1789e1797. doi:10.1136/hrt.2010.204933
 Downloaded from http://heart.bmj.com/ on March 6, 2016 - Published by group.bmj.com
Figure 4 Publication bias and risk of
bias assessments. (A) Funnel plot test
exploring publication bias. (B)
Methodological quality graph: review
authors’ judgements about each
methodological quality item presented
as percentages across all included
studies. (C) Methodological quality
summary: review authors’ judgements
about each methodological quality item
for each included study.
prevalence of this condition and the established role of ASD
closure in the management of these patients, which would not
allow randomisation to a non-repair (placebo) arm.36 60
The validity of any meta-analytical review can potentially be
compromised by heterogeneity in patient characteristics, thera-
peutic intervention or design between studies. The pathophys-
iological complexity of AT makes reviews in this area
particularly prone and vulnerable to heterogeneity. We could not
compare the outcomes for specific ASD sizes or types. Moreover,
the duration of AT is known to affect the response to therapy,
but this information was not available and the analysis may
have included heterogeneous patient groups. Arrhythmia inter-
vention prior to or during surgical intervention is also not
uncommon nowadays and will certainly influence the risk of
arrhythmia after repair. It was not possible to report on the pre-
or post-closure antiarrhythmic pharmacological regimes used or
their impact, since only two studies (Gatzoulis et al and Giardini
et al) provided detailed and specific descriptions of this.
Variation in clinical end-points, their definitions, monitoring
and reporting can also introduce error. Gatzoulis et al,
for example, excluded asymptomatic patients who had
non-sustained AFIB on Holter monitoring.7 Most of the studies
did not report the monitoring methods used for AT and none
Heart 2010;96:1789e1797. doi:10.1136/hrt.2010.204933
Review
specified the duration of each AT. Only four studies used the
same AT monitoring method before and after closure. Further-
more, significant intraoperative factors exist which are known
to potentially influence postoperative arrhythmia outcome, such
as differing surgical practice and variation in the incidence and
management of postoperative complications.
A random-effects model was used to better account for the
inevitable clinical and methodological heterogeneity, however
we were unable to demonstrate significant statistical heteroge-
neity This can be interpreted in two ways: either the various
sources of heterogeneity ‘cancel each other out’ and the absence
of statistical heterogeneity is merely an artefact of the analysis;
or the antiarrhythmic effect that we demonstrate following
ASD closure is readily generalisable to most ASD populations
and closure methods. Examination of the study characteristics
(table 1) suggests the latter.
Implication for further research
Several questions are raised by this study. First, it is important to
establish if the lack of significant statistical heterogeneity among
studies with different patient characteristics, therapeutic inter-
ventions and study designs truly represents the generalisability
of the antiarrhythmic effect of ASD closure or whether it is
1795
 Downloaded from http://heart.bmj.com/ on March 6, 2016 - Published by group.bmj.com
Review
merely an artefact of the analysis. This could take the form of
retrospective analysis of the primary data of included studies, or
a well designed experimental study.
Second, we found that a significant proportion of patients
have persistent AT following ASD closure. The optimum
management of these patients needs to be established. Ablation
for chronic AFIB at the time of surgical ASD closure is well
visited in the literature.7 12 51 61 Giamberti et al describe a series
of 15 patients who were treated with concomitant radio-
frequency ablation during surgical ASD closure, achieving a 93%
reduction in pre-closure AT.62 Joint American Heart Association/
American College of Cardiology guidelines recommend consid-
eration of concomitant Maze procedures in those with inter-
mittent or chronic AT.11 The experience with concomitant
surgical ablation and ASD closure suggests that ablation may
have a role in patients with persistent AT after ASD closure.
However, further research is required to delineate what should
be the indications and timing, especially given the findings in the
literature, supported by this study, which suggest that reverse
remodelling processes are active and that these may not achieve
their maximal effect until some time following ASD closure.
Third, this study suggests that reverse remodelling processes
may have a tangible clinical effect on AT caused by ASD when
the haemodynamic changes resulting from ASD are reversed.
The impact of these reverse remodelling processes on the
cessation of AT at a molecular and cellular level needs to be
better understood and characterised as this could yield novel
therapeutic approaches for AT.
Finally, this study does not provide any evidence of a differ-
ential efficacy in surgical and percutaneous closure techniques
for the termination of AT. As the anatomical indications for both
techniques are different and well defined, further comparison of
the antiarrhythmic effect of these interventions cannot be
justified.11
Conclusions
ASD closure, whether surgical or percutaneous, is associated
with a decrease in the post-closure prevalence of pre-existing AT.
A similar effect was seen in patients after surgical ASD closure
when only AFIB was considered. Further research is required to
establish whether this effect is seen in all patient groups, to
better understand the mechanisms that underlie this treatment
effect and particularly to investigate the role of concomitant
adjunctive antiarrhythmic interventions around the time of
closure.
Funding This work was supported by the National Institute of Health Research
Biomedical Research Centre and British Heart Foundation (RG05/009).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
REFERENCES
1. Campbell M. Natural history of atrial septal defect. Br Heart J 1970;32:820e6.
2. Berger F, Vogel M, Kramer A, et al. Incidence of atrial flutter/fibrillation in adults
with atrial septal defect before and after surgery. Ann Thorac Surg 1999;68:75e8.
3. Craig RJ, Selzer A. Natural history and prognosis of atrial septal defect. Circulation
1968;37:805e15.
4. Murphy JG, Gersh BJ, McGoon MD, et al. Long-term outcome after surgical repair
of isolated atrial septal defect. Follow-up at 27 to 32 years. N Engl J Med
1990;323:1645e50.
5. Webb G, Gatzoulis MA. Atrial septal defects in the adult: recent progress and
overview. Circulation 2006;114:1645e53.
6. Attie F, Rosas M, Granados N, et al. Surgical treatment for secundum atrial septal
defects in patients >40 years old. A randomized clinical trial. J Am Coll Cardiol
2001;38:2035e42.
7. Gatzoulis MA, Freeman MA, Siu SC, et al. Atrial arrhythmia after surgical closure of
atrial septal defects in adults. N Engl J Med 1999;340:839e46.
1796
8. John Sutton MG, Tajik AJ, McGoon DC. Atrial septal defect in patients ages 60
years or older: operative results and long-term postoperative follow-up. Circulation
1981;64:402e9.
9. King TD, Mills NL. Nonoperative closure of atrial septal defects. Surgery
1974;75:383e8.
10. (NICE) NIfCE. Endovascular closure of atrial septal defect. London: National Institute
for Clinical Excellence (NICE), 2004.
11. Warnes CA, Williams RG, Bashore TM, et al. ACC/AHA 2008 Guidelines for the
Management of Adults with Congenital Heart Disease: a report of the American
College of Cardiology/American Heart Association Task Force on Practice Guidelines
(writing committee to develop guidelines on the management of adults with
congenital heart disease). Circulation 2008;118:e714e833.
12. Berger F, Vogel M, Kretschmar O, et al. Arrhythmias in patients with surgically
treated atrial septal defects. Swiss Med Wkly 2005;135:175e8.
13. Taniguchi M, Akagi T, Ohtsuki S, et al. Transcatheter closure of atrial septal defect
in elderly patients with permanent atrial fibrillation. Catheter Cardiovasc Interv
2009;73:682e6.
14. Giardini A, Donti A, Sciarra F, et al. Long-term incidence of atrial fibrillation and
flutter after transcatheter atrial septal defect closure in adults. Int J Cardiol
2009;134:47e51.
15. Wilson NJ, Smith J, Prommete B, et al. Transcatheter closure of secundum atrial
septal defects with the Amplatzer septal occluder in adults and children-follow-up
closure rates, degree of mitral regurgitation and evolution of arrhythmias. Heart Lung
Circ 2008;17:318e24.
16. Spies C, Khandelwal A, Timmermanns I, et al. Incidence of atrial fibrillation
following transcatheter closure of atrial septal defects in adults. Am J Cardiol
2008;102:902e6.
17. Silversides CK, Haberer K, Siu SC, et al. Predictors of atrial arrhythmias after device
closure of secundum type atrial septal defects in adults. Am J Cardiol
2008;101:683e7.
18. Silversides CK, Siu SC, McLaughlin PR, et al. Symptomatic atrial arrhythmias and
transcatheter closure of atrial septal defects in adult patients. Heart 2004;90:1194e8.
19. Suarez De Lezo J, Medina A, Pan M, et al. Transcatheter occlusion of complex
atrial septal defects. Catheter Cardiovasc Interv 2000;51:33e41.
20. Erkut B, Becit N, Unlu Y, et al. The effect of surgical treatment for secundum atrial
septal defect in patients more than 30 years old. Heart Surg Forum 2007;10:
E376e80.
21. Piechowiak M, Banach M, Ruta J, et al. Risk factors for atrial fibrillation in adult
patients in long-term observation following surgical closure of atrial septal defect
type II. Thorac Cardiovasc Surg 2006;54:259e63.
22. Mantovan R, Gatzoulis MA, Pedrocco A, et al. Supraventricular arrhythmia before
and after surgical closure of atrial septal defects: spectrum, prognosis and
management. Europace 2003;5:133e8.
23. Ghosh S, Chatterjee S, Black E, et al. Surgical closure of atrial septal defects in
adults: effect of age at operation on outcome. Heart 2002;88:485e7.
24. Donti A, Bonvicini M, Placci A, et al. Surgical treatment of secundum atrial septal
defect in patients older than 50 years. Ital Heart J 2001;2:428e32.
25. Jemielity M, Dyszkiewicz W, Paluszkiewicz L, et al. Do patients over 40 years
of age benefit from surgical closure of atrial septal defects? Heart
2001;85:300e3.
26. Shibata Y, Abe T, Kuribayashi R, et al. Surgical treatment of isolated secundum
atrial septal defect in patients more than 50 years old. Ann Thorac Surg
1996;62:1096e9.
27. Konstantinides S, Geibel A, Olschewski M, et al. A comparison of surgical
and medical therapy for atrial septal defect in adults. N Engl J Med
1995;333:469e73.
28. Shah D, Azhar M, Oakley CM, et al. Natural history of secundum atrial septal defect in
adults after medical or surgical treatment: a historical prospective study. Br Heart J
1994;71:224e7; discussion 8.
29. Speechly-Dick ME, John R, Pugsley WB, et al. Secundum atrial septal defect
repair: long-term surgical outcome and the problem of late mitral regurgitation.
Postgraduate Med J 1993;69:912e15.
30. Cowen ME, Jeffrey RR, Drakeley MJ, et al. The results of surgery for atrial septal
defect in patients aged fifty years and over. Eur heart J 1990;11:29e34.
31. Brandenburg RO Jr, Holmes DR Jr, Brandenburg RO, et al. Clinical follow-up study
of paroxysmal supraventricular tachyarrhythmias after operative repair of a secundum
type atrial septal defect in adults. Am J Cardiol 1983;51:273e6.
32. Lomholt P. Circumclusion of atrial septal defect in elderly patients. Scand J thorac
cardiovasc surg 1980;14:159e63.
33. Esscher E, Michaelsson M. Long-term results following closure of isolated
ostium secundum atrial septal defect in children and adults. Eur J Cardiol
1977;6:109e16.
34. Saksena FB, Aldridge HE. Atrial septal defect in the older patient. A clinical and
hemodynamic study in patients operated on after age 35. Circulation
1970;42:1009e20.
35. Aldridge HE, Yao J. Secundum atrial septal defect in the adult: repair using
cardiopulmonary bypass in 133 patients. Can Med Assoc J 1967;97:269e74.
36. Athanasiou T, Aziz O, Mangoush O, et al. Does off-pump coronary artery bypass
reduce the incidence of post-operative atrial fibrillation? A question revisited. Eur J
Cardiothorac Surg 2004;26:701e10.
37. The_Cochrane_Library. Cochrane Handbook for Systematic Reviews of Interventions
4.2.5 [updated May 2005]. Chichester, UK: John Wiley & Sons, Ltd, 2005.
Heart 2010;96:1789e1797. doi:10.1136/hrt.2010.204933
 Downloaded from http://heart.bmj.com/ on March 6, 2016 - Published by group.bmj.com

Review

38. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic 51. Oliver JM, Gallego P, Gonzalez A, et al. Predisposing conditions for atrial fibrillation
reviews and meta-analyses: the PRISMA statement. BMJ Clinical research ed in atrial septal defect with and without operative closure. Am J Cardiol
2009;339:b2535. 2002;89:39e43.
39. Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in 52. Gaborit N, Steenman M, Lamirault G, et al. Human atrial ion channel and transporter
epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in subunit gene-expression remodeling associated with valvular heart disease and atrial
Epidemiology (MOOSE) group. Jama 2000;283:2008e12. fibrillation. Circulation 2005;112:471e81.
40. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective 53. Nattel S, Frelin Y, Gaborit N, et al. Ion-channel mRNA-expression profiling: Insights
studies of disease. J Natl Cancer Inst 1959;22:719e48. into cardiac remodeling and arrhythmic substrates. J Mol cell Cardiol 2009.
41. DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlled clin trials 54. Kohl P. Cardiac cellular heterogeneity and remodelling. Cardiovasc res
1986;7:177e88. 2004;64:195e7.
42. Egger M, Smith G, Dg A. Systematic reviews in healthcare: meta-analysis in context. 55. Teo KS, Dundon BK, Molaee P, et al. Percutaneous closure of atrial septal defects
London: BMJ Books, 1995. leads to normalisation of atrial and ventricular volumes. J Cardiovasc Magn Reson
43. Galbraith R. A note on graphical presentation of estimated odds ratios from several 2008;10:55.
clinical trials. Stat Med 1988;7:889e94. 56. Thilen U, Persson S. Closure of atrial septal defect in the adult. Cardiac remodeling
44. Gatzoulis MA, Redington AN, Somerville J, et al. Should atrial septal defects in is an early event. Int J Cardiol 2006;108:370e5.
adults be closed? Ann Thorac Surg 1996;61:657e9. 57. Lo LW, Chen SA. Role of atrial remodeling in patients with atrial fibrillation. J Chin
45. Eckstein J, Verheule S, de Groot NM, et al. Mechanisms of perpetuation of atrial Med Assoc 2007;70:303e9.
fibrillation in chronically dilated atria. Prog Biophysics Mol Biol 2008;97:435e51. 58. Ausma J, van der Velden HM, Lenders MH, et al. Reverse structural and
46. Henry WL, Morganroth J, Pearlman AS, et al. Relation between gap-junctional remodeling after prolonged atrial fibrillation in the goat. Circulation
echocardiographically determined left atrial size and atrial fibrillation. Circulation 2003;107:2051e8.
1976;53:273e9. 59. Kort HW, Balzer DT, Johnson MC. Resolution of right heart enlargement after
47. Morillo CA, Klein GJ, Jones DL, et al. Chronic rapid atrial pacing. Structural, closure of secundum atrial septal defect with transcatheter technique. J Am Coll
functional, and electrophysiological characteristics of a new model of sustained atrial Cardiol 2001;38:1528e32.
fibrillation. Circulation 1995;91:1588e95. 60. Sanchez-Quinones J, Marin F, Roldan V, et al. The impact of statin use on atrial
48. Morton JB, Sanders P, Vohra JK, et al. Effect of chronic right atrial stretch on atrial fibrillation. Qjm 2008;101:845e61.
electrical remodeling in patients with an atrial septal defect. Circulation 61. Bonchek LI, Burlingame MW, Worley SJ, et al. Cox/maze procedure for atrial septal
2003;107:1775e82. defect with atrial fibrillation: management strategies. Ann Thorac Surg
49. Roberts-Thomson KC, John B, Worthley SG, et al. Left atrial remodeling in patients 1993;55:607e10.
with atrial septal defects. Heart Rhythm 2009;6:1000e6. 62. Giamberti A, Chessa M, Foresti S, et al. Combined atrial septal defect surgical
50. Satoh T, Zipes DP. Unequal atrial stretch in dogs increases dispersion of refractoriness closure and irrigated radiofrequency ablation in adult patients. Ann Thorac Surg
conducive to developing atrial fibrillation. J Cardiovasc Electrophysiol 1996;7:833e42. 2006;82:1327e31.

Heart 2010;96:1789e1797. doi:10.1136/hrt.2010.204933 1797

 Downloaded from http://heart.bmj.com/ on March 6, 2016 - Published by group.bmj.com

Atrial septal defect closure is associated with

a reduced prevalence of atrial
tachyarrhythmia in the short to medium term:
a systematic review and meta-analysis
Joshua A Vecht, Srdjan Saso, Christopher Rao, Konstantinos
Dimopoulos, Julia Grapsa, Cesare M Terracciano, Nicholas S Peters,
Petros Nihoyannopoulos, Elaine Holmes, Michael A Gatzoulis and
Thanos Athanasiou

Heart 2010 96: 1789-1797

doi: 10.1136/hrt.2010.204933

Updated information and services can be found at:

http://heart.bmj.com/content/96/22/1789

These include:

References This article cites 58 articles, 22 of which you can access for free at:
http://heart.bmj.com/content/96/22/1789#BIBL

Email alerting Receive free email alerts when new articles cite this article. Sign up in the
service box at the top right corner of the online article.

Notes

To request permissions go to:

http://group.bmj.com/group/rights-licensing/permissions

To order reprints go to:

http://journals.bmj.com/cgi/reprintform

To subscribe to BMJ go to:

http://group.bmj.com/subscribe/